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Growth inhibition of adult T-cell leukemia cells through the Toll-like receptor signaling

Research Project

Project/Area Number 17591018
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionUniversity of Occupational and Environmental Health, Japan

Principal Investigator

TSUKADA Junichi  University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 助教授 (20227367)

Co-Investigator(Kenkyū-buntansha) OSADA Yoshio  University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (80282515)
YOSHIDA Yasuhiro  University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (10309958)
UENO Susumu  University of Occupational and Environmental Health, Japan, School of Medicine, Assistant Professor, 医学部, 講師 (00279324)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsadult T-cell leukemia / Toll-like receptor / MyD88 / Toll likeレセプター
Research Abstract

Constitutive activation of nuclear factor-κB (NF-κB) is a common feature of adult T-cell leukemia (ATL). Although the mechanism by which NF-κB is spontaneously activated in ATL cells still remains unclear, inhibition of NF-κB activity induces apoptosis of ATL cells, suggesting a central role of NF-κB in their proliferation.
In this study, we investigated whether MyD88, adaptor protein of Toll-like receptor (TLR) signaling, participate constitutive activation of NF-κB in HTLV-I-transformed T-cells.
HTLV-I transformed T-cell line MT2 was used in this experiment. The effect of MyD88dn expression on activation of transcription factors and cytokine promoters by luciferase assay, proliferation and apoptosis were studied.
We demonstrated constitutive association of MyD88, an adaptor protein for the TLR signaling, with the IL-1R-associated kinase 1 (IRAK1) in HTLV-I-transformed T-cells, MT2 and HUT102. In MT2 cells, constitutive activation of NF-κB and NF-IL6, but not Stat3 was significantly inhibited by expression of MyD88dn. Spontaneous transcriptional activation of IL-1a, IFN-γ and TNF-α gene promoters in MT2 cells was also suppressed by MyD88dn expression. MyD88dn inhibited cell proliferation and induced apoptosis of MT2 cells. In addition, HTLV-I Tax synergistically activated NF-κB with wild-type MyD88.
Our results show a critical role of MyD88 in dysregulated gene activation and cell proliferation in HTLV-I-transformed T-cells. Considering the fact that blocking NF-κB is a potential strategy to treat ATL, our data further suggest a possibility of new treatment target molecules existing.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (14 results)

All 2007 2006 2005

All Journal Article (14 results)

  • [Journal Article] Phosphorylation of IRF8 in a pre-associated complex with Spi-1/PU.1 and non-phosphorylated Stat1 is critical for LPS induction of the IL1B gene.2007

    • Author(s)
      Unlu S, Kumar A, Waterman WR, Tsukada J, Wang KZ, Galson DL, Auron PE
    • Journal Title

      Mol Immunol 44(13)

      Pages: 3364-3379

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Auron PE Phosphorylation of IRF8 in a pre-associated complex with Spi-1/PU. 1 and non-phosphorylated Statl is critical for LPS induction of the IL1B gene.2007

    • Author(s)
      Unlu S, Kumar A, Waterman WR, Tsukada J, Wang KZ, Galson DL
    • Journal Title

      Mol Immunol. 44(13)

      Pages: 3364-79

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP6001252006

    • Author(s)
      Wang B, Tsukada J, Higashi T, Mizobe T, Matsuura A, Mouri F, Sawamukai N, Ra C, Tanaka Y
    • Journal Title

      Genes Cells 11(9)

      Pages: 983-992

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glucocorticoid inhibits the human pro-interleukin 1beta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer.2006

    • Author(s)
      Waterman WR, Xu LL, Tetradis S, Motyckova G, Tsukada J, Saito K, Webb AC, Robinson DR, Auron PE
    • Journal Title

      Mol Immunol 43(7)

      Pages: 773-782

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan. 20062006

    • Author(s)
      Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N, Furukawa T, Tsukada J, Takeda H, Aizawa Y, Harada M
    • Journal Title

      Bone Marrow Transplant. 38(10)

      Pages: 681-686

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Retrospective analysis of cord blood transplantation on 62 adult patients with advanced hematological malignancies.2006

    • Author(s)
      Tamura K, Kawano F, Etoh T, Utsunomiya A, Imamura Y, Okamura S, Tsukada J, Uike N, Takamatsu Y, Kyushu Hematology Organization for Treatment Study Group.
    • Journal Title

      Fukuoka Igaku Zasshi. 97(6)

      Pages: 175-182

    • NAID

      120002548748

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glucocorticoid inhibits the human pro-interleukin lbeta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer2006

    • Author(s)
      Waterman WR, Xu LL, Tetradis S, Motyckova G, Tsukada J, Saito K, Webb AC, Robinson DR, Auron PE.
    • Journal Title

      Mol Immunol. 43(7)

      Pages: 773-782

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mismatch of minor histocompatibility antigen contributes to a graft-versus-leukemia effect rather than to acute GVHD, resulting in long-term survival after HLA-identical stem cell transplantation in Japan.2006

    • Author(s)
      Katagiri T, Shiobara S, Nakao S, Wakano M, Muranaka E, Kuba N, Furukawa T, Tsukada J, Takeda H, Aizawa Y, Harada M.
    • Journal Title

      Bone Marrow Transplant. 38(10)

      Pages: 681-686

    • NAID

      120000809813

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125.2006

    • Author(s)
      Wang B, Tsukada J.Higashi T, Mizobe T, Matsuura A, Mouri F, Sawamukai N, Ra C, Tanaka Y.
    • Journal Title

      Genes Cells. 11(9)

      Pages: 983-992

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Kyushu Hematology Organization for Treatment Study Group. Retrospective analysis of cord blood transplantation on 62 adult patients with advanced hematological malignancies.2006

    • Author(s)
      Tamura K, Kawano F, Etoh T, Utsunomiya A, Imamura Y, Okamura S, Tsukada J, Uike N, Takamatsu Y
    • Journal Title

      Fukuoka Igaku Zasshi. 97(6)

      Pages: 175-82

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glucocorticoid inhibits the human pro-interleukin 1β gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer.2006

    • Author(s)
      Waterman WR et al.
    • Journal Title

      Molecular Immunology 43(7)

      Pages: 773-778

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I2005

    • Author(s)
      Higashi T, Tsukada J, Yoshida Y, Mizobe T, Mouri F, Minami Y, Tanaka Y
    • Journal Title

      Genes to Cell 10(12)

      Pages: 1153-1162

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I2005

    • Author(s)
      Higashi T, Tsukada J, Yoshida Y, Mizobe T, Mouri F, Minami Y, Tanaka Y
    • Journal Title

      Genes to Cells 10(12)

      Pages: 1153-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I.2005

    • Author(s)
      Higashi T et al.
    • Journal Title

      Genes to Cells 10(12)

      Pages: 1153-1162

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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